Genetics of Pheochromocytoma and Paraganglioma: Hereditary Syndromes and Genetic Testing
If you are new to this subject, start with our pheochromocytoma overview. Pheochromocytomas and paragangliomas are rare tumors, but they are inherited more often than almost any other tumor: about 30–40% are caused by an inherited change (a pathogenic variant, or mutation) in a tumor-susceptibility gene. For this reason genetic testing and counseling should be offered to every patient with a pheochromocytoma or paraganglioma, whatever their age and whether or not there is a family history. Dr. Carling, who founded and directed the Yale Endocrine Neoplasia Laboratory, has focused much of his scientific work on this area. Genetic testing is widely available today, but it is still underused because of lack of knowledge and, occasionally, fear. A positive test lets us find and treat tumors early in the patient, and in their children and other family members, sometimes before symptoms occur. It can also change the operation that is planned. A negative test can bring enormous relief and save the patient and family members unnecessary and costly scans and tests.
Pheochromocytomas and Paragangliomas: How Common, and How Often Hereditary?
A note from the team at the Carling Adrenal Center: some of the information on this page is technical, even for clinical endocrinologists and clinical geneticists. We include it because many referring doctors and patients benefit from understanding it.
The incidence of pheochromocytomas and paragangliomas in the general population is about 0.6 cases/100,000 per year. Historical teaching (the "rule of 10s") was that 10% of pheochromocytomas and paragangliomas are hereditary. That teaching is outdated: with the discovery of the syndromes caused by pathogenic variants in the SDHx, TMEM127, and MAX genes, we now know that about 30–40% of pheochromocytomas and paragangliomas are hereditary, and in children the figure is around 70–80%. All pheochromocytomas and paragangliomas are now considered to have metastatic potential, so they are no longer classified as "benign" or "malignant"; most never spread, and the reported proportion that become metastatic varies widely between studies. Most metastatic pheochromocytomas and paragangliomas are functional and cause catecholamine excess (adrenaline-type hormone production). The outlook with metastatic disease also varies widely. The well-established pheochromocytoma susceptibility genes include RET, VHL, NF1, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, MAX and FH. An inherited (germline) variant in one of these genes is found in most familial cases and also in a meaningful share of patients with no family history at all, which is why testing is not limited to people with affected relatives. Of note, MEN1 syndrome has also been very rarely associated with pheochromocytoma but is more typically linked to adrenocortical tumors.
In addition to germline mutations in the pheochromocytoma susceptibility genes, many somatic mutations have been discovered in sporadic pheochromocytoma. All pheochromocytomas and paragangliomas -associated genes discovered to date can be grouped into 3 clusters. These clusters are thought to represent distinct pathways of pheochromocytoma tumorigenesis.
• Cluster 1, known as the “pseudohypoxia subtype”, consists of genes related to cell metabolism and the hypoxia response and includes the SDHx and VHL genes. The SDHx genes encode for subunits of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, SDHD) and an assembly factor, SDHAF2. SDH and VHL both play roles in the ubiquitination and destruction process of hypoxia-inducible factor (HIF). Defects in either protein can lead to constitutive activation of the hypoxia-angiogenesis pathway. Mutations in the FH (fumarate hydratase) and EPAS1/HIF2A genes, which are involved in the hypoxia response, occur in some sporadic pheochromocytomas and paragangliomas.
• Cluster 2 represents dysregulation of kinase signaling pathways. This cluster includes the RET, NF1, TMEM127, and MAX genes. RET and NF1 are well-known players in tumorigenesis and are involved in multiple cell signaling pathways that regulate cell differentiation, survival and proliferation. MAX is a transcription factor identified as a pheochromocytoma and paraganglioma susceptibility gene through genome sequencing. TMEM127 was discovered through linkage studies, transcription expression profiling and copy-number mapping and encodes a transmembrane protein that is thought to regulate protein trafficking and the mTOR pathway. Somatic mutations in this cluster include the H-RAS and ATRX mutations found in some sporadic pheochromocytomas and paragangliomas.
• Cluster 3 is the Wnt signaling group and is represented by somatic mutations in the gene CSDE1 and fusions involving the gene MAML3. Mutations in CSDE1 lead to down-regulation of apoptosis while MAML3 gene mutations are associated with hypomethylation, β-catenin overexpression and Wnt signaling upregulation. Cluster 3 appears to be associated with more aggressive disease and poorer prognosis. Germline mutations have not been identified thus far in this cluster.
How a hereditary pheochromocytoma or paraganglioma behaves depends on which gene is involved. The pheochromocytomas of MEN2 (RET), for example, are nearly always adrenal in location, often bilateral, and carry a low risk of metastasis. Pheochromocytomas and paragangliomas in VHL also have a low risk of metastasis but are associated with other tumors such as retinal angiomas, CNS hemangioblastomas, renal cell carcinoma and pancreatic neuroendocrine tumors. On the other hand, SDHD variants are associated with head and neck paraganglioma, and SDHB carries the highest risk of metastatic disease of all the susceptibility genes.
Who Should Have Genetic Testing and Counseling?
Every patient diagnosed with a pheochromocytoma or paraganglioma should be offered genetic testing and counseling, given how often these tumors are hereditary. Pheochromocytoma and paraganglioma are more often associated with an inherited disorder than other adrenal tumors. Early onset of disease, multiple tumors at the same time, recurrence, metastases, and a positive family history are strongly suggestive of a hereditary syndrome, but a hereditary cause is also found in patients with none of these features.
Detailed personal and family history taking should focus on the presence of syndrome-associated features such as history of medullary thyroid cancer and hyperparathyroidism (MEN2); history of CNS hemangioblastomas and renal cell carcinomas (VHL), and history of GIST, papillary thyroid cancer, pituitary adenomas, and other neuroendocrine tumors (hereditary pheochromocytoma/paraganglioma syndromes). Suspicion for a specific syndrome may be increased or decreased based on the presence of these associated features. Variants in RET and VHL can be detected by single-gene testing, and neurofibromatosis type 1 is usually recognized from its clinical features. In practice, genetic testing is now most often performed with a multigene panel that includes all the known causative genes (RET, VHL, NF1, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, MAX and others).
Hereditary Pheochromocytoma Syndromes
MEN2
MEN2 patients have about a 50% chance of developing pheochromocytoma; the exact risk depends on the location of their RET mutation, and those involving codon 634 appear to have the highest risk. Pheochromocytomas in MEN2 are almost always limited to the adrenal glands, often bilateral, and rarely metastatic. MEN2B is most often diagnosed in childhood due to the early onset of medullary thyroid cancer (MTC), but 13-27% of MEN2A patients present with pheochromocytoma as the initial diagnosis. It is important to identify this group of patients as they may benefit from prophylactic thyroidectomy and/or medullary thyroid cancer screening. See our page on pheochromocytoma in MEN2.
Von Hippel-Lindau
VHL is caused by pathogenic mutations in the VHL gene and is inherited in an autosomal dominant manner. About 20% of cases are caused by de novo mutations. In addition to pheochromocytoma and paraganglioma, patients with VHL are predisposed to developing retinal angiomas, CNS hemangioblastomas, renal clear cell carcinoma and cysts, endolymphatic sac tumors, and other neuroendocrine tumors. The life-time risk of developing pheochromocytoma and paraganglioma in VHL is 10-25%, and they have a low risk of metastasis. There are two major sub-types of VHL: type I and type II. VHL type I is associated with truncating mutations and deletions of exons or the entire VHL gene. It carries a high risk for retinal angiomas and CNS hemangioblastomas but a relatively low risk for pheochromocytoma and paraganglioma. VHL type II is associated with missense variants and carries a relatively high risk for pheochromocytoma and paraganglioma.
Neurofibromatosis 1
Neurofibromatosis 1 is a genetic disorder commonly associated with café-au-lait spots, cutaneous neurofibromas, Lisch nodules, CNS gliomas and peripheral nerve sheath tumors. It is caused by loss-of-function mutations of the NF1 tumor suppressor gene. While pheochromocytoma is not a typical tumor of neurofibromatosis 1, 0.1-5.7% of patients with NF1 will develop a pheochromocytoma or paraganglioma, a frequency that is higher than that of the general population. Up to 12% of pheochromocytomas and paragangliomas in NF1 are metastatic. Interestingly, many sporadic pheochromocytomas and paragangliomas have been found to have somatic NF1 gene mutations, supporting the hypothesis that the NF1 gene plays a role in how these tumors form.
Hereditary pheochromocytoma and paraganglioma syndromes (SDHx, TMEM127, MAX)
Hereditary pheochromocytoma and paraganglioma syndromes are a group of disorders caused by germline pathogenic variants in the SDHx, TMEM127, and MAX genes that predispose to the development of pheochromocytoma and paraganglioma as well as certain other tumors such as gastrointestinal stromal tumors (GIST), renal cell carcinoma (RCC), and possibly thyroid and pituitary tumors in some cases. All are inherited in an autosomal dominant manner, but MAX, SDHAF2, and SDHD show a parent-of-origin effect: tumors develop almost only when the gene change is inherited from the father. There appears to be an association between SDHA variants and gastrointestinal stromal tumors (GIST) as well.
SDHB pathogenic variants are associated with the highest risk of metastatic disease. Patients with SDHB variants can develop pheochromocytoma and paraganglioma and may have multiple tumors. Up to 50% of patients with metastatic pheochromocytoma and paraganglioma have a germline variant of SDHB. In addition, patients have a higher risk of developing renal tumors including renal clear cell carcinoma, GIST, papillary thyroid cancer, and pituitary adenomas.
SDHC pathogenic variants display a phenotype like SDHAF2 variants and are mainly associated with head and neck paragangliomas. However, paragangliomas in the chest occur up to 10% of the time. Patients may also be at increased risk of developing GIST.
SDHD pathogenic variants are most frequently associated with head and neck paraganglioma. Adrenal pheochromocytomas and paragangliomas in other locations also occur. They are also associated with GIST, RCC, pituitary and thyroid tumors.
SDHAF2 pathogenic variants have only been associated with head and neck paragangliomas. They do not appear to carry a risk for other tumors.
TMEM127 pathogenic variants are associated with pheochromocytoma and paraganglioma and may also increase the risk of renal cell carcinoma.
MAX pathogenic variants are associated with pheochromocytoma and more rarely paraganglioma.
How Do You Care for Patients at Increased Risk Because of an Inherited Gene Change?
MEN2
Patients with MEN2 should undergo screening for pheochromocytoma, MTC and hyperparathyroidism based on ATA recommendations. Patients in the highest-risk and high-risk categories should have yearly biochemical screening for pheochromocytoma beginning at age 11. Patients in the moderate risk category should have yearly biochemical screening for pheochromocytoma beginning at age 16.
Von Hippel-Lindau (VHL)
Several groups have proposed recommendations for tumor screening in VHL. Most advocate for annual history and physical examination including blood pressure and neurologic evaluation, eye and retinal exams every 1-2 years, annual plasma free metanephrines, audiology evaluation every 2-3 years, brain MRI every 1-2 years, and annual abdominal ultrasound or CT/MRI. The age at which to start screening is also debated with most recommending retinal exams starting from birth-2 years, pheochromocytoma screening starting from age 2, audiology exams starting from age 5, brain imaging starting from age 8, and abdominal imaging starting from age 10.
Neurofibromatosis 1
There is no single agreed screening schedule for patients with neurofibromatosis 1. Clinicians should be aware of the higher prevalence of pheochromocytoma and paraganglioma in NF1. These tumors should be suspected based on clinical signs and symptoms, and testing proceeds in the usual way with plasma free metanephrines or 24-hour urine fractionated metanephrines.
Hereditary pheochromocytoma and paraganglioma syndromes
Recommendations for the management and screening of patients with SDHx, TMEM127, and MAX gene variants differ between expert groups. It is reasonable to perform screening with annual history and physical examination, blood pressure measurement, plasma free metanephrines or 24-hour urine fractionated metanephrines, and cross-sectional whole-body imaging every 1-2 years. Pediatric patients should be started on lifelong surveillance after age 6-8. MRI is used for pediatric or pregnant patients to minimize radiation exposure. Routine surveillance for GIST has not been recommended, but patients with unexplained gastrointestinal symptoms should undergo evaluation for a GIST.
Why the Gene Result Matters for Surgery and Follow-Up
Knowing the gene before surgery can change the operation. People with hereditary pheochromocytomas (especially MEN2 and VHL) often develop tumors in both adrenal glands, at the same time or years apart. For them, adrenal-sparing surgery (partial adrenalectomy), which removes the tumor but preserves healthy adrenal cortex, can often avoid lifelong steroid dependence. The trade-off is that a new pheochromocytoma can grow in the remaining adrenal tissue: this happened in about 13% of patients in the largest international registry, usually many years later. Everyone who has had a pheochromocytoma, hereditary or not, needs lifelong follow-up with a metanephrine test every year. Read more about surgery for pheochromocytoma and adrenal-sparing surgery.
Last updated October 2026.